A zebra’s stripes, a seashell’s spirals, a butterfly’s wings: these are all examples of patterns in nature. The formation of patterns is a puzzle for mathematicians and biologists alike. How does the delicate design of a butterfly’s wings come from a single fertilized egg? How does pattern emerge out of no pattern?
Using computer models and live cells, researchers at Johns Hopkins have discovered a specific pattern that can direct cell movement and may help us understand how metastatic cancer cells move.
“Pattern formation is a classic problem in embryology,” says Denise Montell, Ph.D., a professor of biological chemistry at Hopkins. “At some point, cells in an embryo must separate into those that will become heart cells, liver cells, blood cells and so on. Although this has been studied for years, there is still a lot we don’t understand.”
As an example of pattern formation, the researchers studied the process of how about six cells in the fruit fly distinguish themselves from neighboring cells and move from one location in the ovary to another during egg development. “In order for this cell migration to happen, you have to have cells that go and cells that stay,” says Montell. “There must be a clear distinction — a separation between different types of cells, which on the surface look the same.”
Previous work identified a specific signal necessary for getting these fly egg cells to move; the problem is that this signal is “graded.” Like drops of ink spreading out on wet paper, this signal travels in between surrounding cells, gradually fading away as it moves outwards. But clear lines are required for pattern formation — there is no grey area between a zebra’s black and white stripes, between heart and liver cells and, in this case, between migrating cells and those that stay put.
How are graded signals converted to a clear move or stay signal? By examining flies containing mutations in different genes, the researchers discovered that one gene in particular, called apontic, is important for converting a graded signal. “When apontic is mutated, the distinction between migrating and nonmigrating cells is fuzzy,” says Michelle Starz-Gaiano, Ph.D., a postdoctoral fellow in biological chemistry. “In these mutants, we see a lot of cases where migrating cells do not properly detach from their neighbors but instead drag them along as they move away.” This showed that the graded signal alone was not sufficient to kick-start the proper number of cells, but instead needed help from apontic.
Once the team discovered that apontic is important for getting these cells to move, they set out to figure out how apontic works. Collaborating with mathematician Hans Meinhardt, Ph.D., a professor emeritus at the Max Planck Institute in Germany, they designed a computer model that could simulate how graded signals are converted to commands that tell cells to move or to stay.
By making certain assumptions about each gene and assigning functions to each protein, the team built a simple circuit that can predict a cell’s behavior using the graded signal, apontic, and another previously discovered protein called slbo (pronounced “slow-bo”). The computer model shows that in a cell, the graded signal turns on both apontic and slbo. But apontic and slbo work against and battle each other: when one gains a slight advantage, the other weakens, which in turn causes the first to gain an even bigger advantage. This continues until one dominates in each cell. If slbo wins, the cell moves but if apontic wins, the cell stays put; thus a clear separation between move or stay is achieved.
“Not only is this a new solution to the problem of how to create a pattern out of no pattern, but we have also discovered that apontic is a new regulator of cell migration,” says Montell.
Cell migration likely underlies the spreading of cancer cells beyond an original tumor to other areas of the body. Understanding and therefore being able to manipulate the cell migration pathway could potentially prevent the development of these new tumors. At this stage, Montell says, “it’s more about just understanding what the positive and negative regulators of cell migration are.”
The research was funded by the American Cancer Society and the National Institutes of Health.
This study was published in the May 13 issue of Developmental Cell. Authors on the paper are Starz-Gaiano, Mariana Melani, Xiaobo Wang, and Montell, all of Hopkins; and Hans Meinhardt of the Max-Planck-Institut, Tübingen, Germany.
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